Supplementary Information

Metal Complex Derivatives of Azole: a Study on Their Synthesis, Characterization, and

Antibacterial and Antifungal Activities

Keshia F. Castillo,a,#

Nestor J. Bello-Vieda,b,#

Nelson G. Nuñez-Dallos,b Homero F. Pastrana,

c Adriana

M. Celis,a Silvia Restrepo,

a John J. Hurtado*

,b and Alba G. Ávila

c

aDepartamento de Ciencias Biológicas, Laboratorio de Micología y Fitopatología,

bDepartamento de

Química, Grupo de Investigación en Química Inorgánica, Catálisis y Bioinorgánica and cDepartamento

de Ingeniería Eléctrica y Electrónica, Centro de Microelectrónica, Universidad de Los Andes, Bogotá

D.C., Colombia

Synthesis of ligands

Bis(3,5-dimethyl-1-pyrazolyl)methane (2)

This ligand was prepared by using a modified procedure from the literature.1 In a Schlenk tube equipped with a

reflux condenser, 3,5-dimethyl-1H-pyrazole (31.2 mmol; 3.0 g), KOH (48.13 mmol; 2.7 g), potassium carbonate

(47.75 mmol; 6.6 g), tetrabutylammonium bromide (2.39 mmol; 0.77 g) and 30 mL of dichloromethane were added

and the mixture was refluxed for 36 h. To the resulting mixture, a liquid-liquid extraction was performed with

3-20 mL volumes of water. The organic layer was separated and dried over magnesium sulfate, and the solvent was

evaporated to dryness. The resulting white solid was purified by silica gel column chromatography (type 60) by

using dichloromethane:methanol (30:1) as an eluent. Yield: 2.68 g (84%); mp: 105-106 °C; IR (KBr) ν / cm-1

2980,

1557, 1353, 1267, 1035, 776; 1H NMR (400.1 MHz, DMSO-d6) δ 6.03 (s, 2H), 5.81 (s, 2H), 2.39 (s, 6H), 2.06 (s,

6H); anal. calcd. for C11H16N4: C 64.68, H 7.90, N 27.43; found: C 64.64, H 7.82, N 27.42%; HRMS (FTMS +

pESI) m/z, calcd. for [M + H]+: 205.1448; found: 205.1452.

Bis(1,2,4-triazol-1-yl)methane (3)

This ligand was prepared by using a modified procedure from the literature.2 In a Schlenk tube equipped with a

reflux condenser, 1H-1,2,4-triazole (13.3 mmol; 920.6 mg), KOH (44.85 mmol; 2.5167 g) and water (1 mL) were

stirred at room temperature (rt) for 60 min, and then tetrabutylammonium bromide (0.473 mmol, 152.8 mg) and

dichloromethane (50 mL) were added. This mixture was refluxed for 48 h. The resulting mixture was filtered off and

treated with water, and the organic layer was separated and dried with magnesium sulfate. The solution was

*e-mail: jj.hurtado@uniandes.edu.co #These authors contributed equally to this work

evaporated to dryness to give a white solid. The compound was purified by silica gel column chromatography (type

60) using acetone as an eluent. Yield: 1.004 g (66%); mp: 142-143 °C; IR (KBr) ν / cm-1

3115, 3021, 1812, 1507,

1422, 1275, 1202, 1131, 1021, 876, 673; 1H NMR (400.1 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.04 (s, 1H), 6.65 (s, 1H);

anal. calcd. for C5H6N6: C 40.00, H 4.03, N 55.97; found: C 39.97, H 3.95, N 55.92%; HRMS (FTMS + pESI) m/z,

calcd. for [M + H]+: 151.0727; found: 151.0743.

3,5-Bis(3,5-dimethylpyrazol-1-ylmethyl)toluene (4)

The ligand (4) was synthetized by modifying a procedure from the literature.3 In a Schlenk tube equipped with a

reflux condenser, 3,5-dimethyl-1H-pyrazole (10.41 mmol; 1.001 g), KOH (28.96 mmol; 1.157 g) and water (1 mL)

were stirred at rt for 30 min, and then tetrabutylammonium bromide (0.332 mmol; 107.0 mg) and 3,5-

bis(bromomethyl)toluene (0.005 mmol; 1.3406 g) and 20 mL of toluene were added. The mixture was refluxed for

48 h. The resulting mixture was evaporated to dryness and the solid residue was extracted with

dichloromethane:water. The organic phase was collected and dried with anhydride sodium sulfate. The ligand was

purified by column chromatography using dichloromethane:ethyl acetate (7:3) as the eluent. Yield: 1.004 g (68%);

mp: 92 °C; IR (KBr) ν / cm-1

2927, 1605, 1553, 1462, 1351, 1214, 775; 1H NMR (400.1 MHz, DMSO-d6) δ 6.75 (s,

2H), 6.54 (d, 1H, J 11.1 Hz), 5.82 (s, 2H), 5.10 (d, 4H, J 8.1 Hz), 2.44-1.81 (m, 15H); anal. calcd. for C19H24N4:

C 73.99, H 7.84, N 18.17; found: C 74.01, H 7.82, N 18.1%; HRMS (FTMS + pESI) m/z, calcd. for [M + H]+:

309.2074; found: 309.2100.

2,6-Bis(benzotriazol-1-ylmethyl)pyridine (5)

The ligand was prepared by following a procedure that was modified from the literature.4-6

A solution of 1H-

benzotriazole (2.51 mmol; 299.2 mg) in 32 mL of toluene was added to 2,6-bis(bromomethyl)pyridine (2.51 mmol;

333.4 mg). The reaction mixture was refluxed for 48 h. The resulting mixture was filtered off, concentrated and

cooled at 4 °C for 2 days to obtain a white solid that was washed with diethyl ether and re-crystallized with

chloroform:diethyl ether (1:1). Yield: 246 mg (57%); mp: 121-123 °C; IR (KBr) ν / cm-1

3067, 3033, 2977, 2948,

1596, 1575, 1455, 1428, 1225, 1158, 1092, 785, 742; 1H NMR (400.1 MHz, DMSO-d6) δ 8.03 (dd, 2H, J 6.1,

2.4 Hz), 7.80 (t, 1H, J 7.8 Hz), 7.54 (dd, 2H, J 6.4, 2.5 Hz), 7.43-7.33 (m, 4H), 7.26 (d, 2H, J 7.8 Hz), 6.00 (s, 4H),

anal. calcd. for C19H15N7: C 66.85, H 4.43, N 28.72; found: C 66.88, H 4.43, N 28.70%; HRMS (FTMS + pESI) m/z,

calcd. for [M + H]+: 342.1462; found: 342.1468.

3,5-Bis(benzotriazol-1-ylmethyl)toluene (6)

This ligand was prepared by following a method reported in the literature7 with some modifications. In a

Schlenk tube equipped with a reflux condenser, 1H-benzotriazole (2.83 mmol; 336.8 mg),

3,5-bis(bromomethyl)toluene (1.41 mmol; 391.9 mg) and toluene (10 mL) were added and the mixture was heated

and refluxed for 48 h. The resulting mixture was filtered off and the toluene solution was cooled (−15 °C) for 48 h.

The precipitated product was filtered and washed with diethyl ether. Yield: 214.5 mg (43%); mp: 147-148 °C; IR

(KBr) ν / cm-1

: 1613, 1495, 1453, 1308, 1221, 1130, 1093, 781, 745; 1H NMR (400.1 MHz, CDCl3) δ 8.03 (d, 2H,

J 8.3 Hz), 7.70 (d, 2H, J 8.3 Hz), 7.46 (t, 2H, J 7.5 Hz), 7.41-7.33 (m, 2H), 7.15 (s, 1H), 7.09 (s, 2H), 5.89 (s, 4H),

2.19 (s, 3H); anal. calcd. for C21H18N4: C 71.17, H 5.12, N 23.71; found: C 71.12, H 5.10, N 23.60%; HRMS

(FTMS + pESI) m/z, calcd. for [M + H]+: 355.1666; found: 355.1685.

Synthesis of complexes

Dichloro[bis(3,5-dimethylpyrazole-NN)]zinc(II) (8)

The crystal structure of this complex was found,8 but the experimental procedures for the synthesis were not

available, and the following procedures produced the desired complex. In a Schlenk tube equipped with a reflux

condenser, 3,5-dimethylpyrazole (1) (6.24 mmol; 600.1 mg), zinc(II) chloride (2.74 mmol; 374.1 mg) and ethanol

(15 mL) were added and the mixture was heated and refluxed for 7 h. The reaction mixture was cooled at −5 °C for

24 h to afford a white solid, which was washed repeatedly with cool ethanol and dried under a vacuum. Yield:

679.5 mg (76%); mp: 229-230 °C; IR (KBr) ν / cm-1

3346, 3316, 3144, 2925, 1570, 1471, 1409, 1272, 1168, 1048,

820, 427; 1H NMR (400.1 MHz, DMSO-d6) δ 12.13 (s, 1H), 5.82 (s, 1H), 2.15 (s, 6H); anal. calcd. for

C10H16Cl2N4Zn: C 36.56, H 4.91, N 17.05; found: C 36.50, H 4.90, N 17.04%.

Dichloro[bis(3,5-dimethyl-1-pyrazolyl)methane-NN]zinc(II) (9)

This compound was obtained by following a procedure similar to that of a previous report.9 A solution of

bis(3,5-dimethyl-1-pyrazolyl)methane (2) (0.518 mmol; 105.9 mg) in 2 mL of ethanol was added via syringe to a

zinc(II) chloride solution (0.489 mmol; 66.7 mg) in 2 mL of ethanol. A white solid precipitate was produced

immediately. The product was filtered off and washed with ethanol and hexane. Yield: 125.7 mg (75%);

mp: > 300 °C; IR (KBr) ν / cm-1

3015, 1558, 1466, 1392, 1280, 1051, 1006, 829, 805, 677, 494; 1H NMR

(400.1 MHz, DMSO-d6) δ 6.04 (s, 2H), 5.82 (s, 2H), 2.39 (s, 6H), 2.06 (s, 6H); anal. calcd. for C11H16Cl2N4Zn:

C 38.80, H 4.74, N 16.45; found: C 38.76, H 4.72, N 16.43%.

Dichloro[bis(1,2,4-triazol-1-yl)methane-NN]zinc(II) (10)

This compound was obtained by following a modification of published methods.10

A solution of bis(1,2,4-

triazol-1-yl)methane (3) (1.33 mmol; 200.1 mg) in 5 mL of ethanol was added to a solution of zinc(II) chloride

(1.35 mmol; 184.5 mg) in 3 mL of ethanol. A white solid precipitate was produced immediately, which was filtered

off and washed with ethanol and diethyl ether. Yield: 360.1 mg (94%); mp: > 300 °C; IR (KBr) ν / cm-1

3120, 1535,

1465, 1286, 1209, 1128, 737, 669, 505; 1H NMR (400.1 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.06 (s, 1H), 6.66 (s, 1H);

anal. calcd. for C5H6Cl2N6Zn: C 20.97, H 2.11, N 29.34; found: C 20.92, H 2.11, N 29.24%.

Dichloro[bis(3,5-dimethyl-1-pyrazolyl)methane-NN]copper(II) (15)

The compound was obtained according to a previous report.11

A solution of bis(3,5-dimethyl-1-

pyrazolyl)methane (2) (1.47 mmol; 300 mg) in 6 mL of acetone was added to a solution of CuCl2.2H2O (1.48 mmol;

253 mg) in 2 mL of acetone. The reaction mixture was stirred at rt for 30 min. The yellow solid was filtered off,

washed with acetone and diethyl ether and dried at 80 °C for 6 h. Yield: 234 mg (78%); mp: 206-207 °C; IR (KBr)

ν / cm-1

3027, 1558, 1467, 1386, 1279, 1044, 785, 677, 492; anal. calcd. for C11H16Cl2N4Cu: C 39.01, H 4.76,

N 16.54; found: C 39.01, H 4.75, N 16.44%.

Dichloro[bis(3,5-dimethyl-1-pyrazolyl)methane-NN]cobalt(II) (16)

This complex was prepared by following a method reported in the literature.12

A solution of bis(3,5-dimethyl-1-

pyrazolyl)methane (2) (0.5 mmol; 101 mg) in 3 mL of methanol was added to a CoCl2.6H2O solution (0.53 mmol;

126 mg) in 2 mL of methanol. The reaction mixture was stirred at rt for 60 min. The blue solid was filtered off and

washed with methanol and diethyl ether. Yield: 58.2 mg (57%); mp: > 300 °C; IR (KBr) ν / cm-1

3133, 1556, 1465,

1390, 1278, 1051, 807, 677, 493; anal. calcd. for C11H16Cl2N4Co: C 39.54, H 4.83, N 16.77; found: C 39.52, H 4.76,

N 16.74%.

Figure S1. 1H NMR (400.1 MHz, DMSO-d6) of 1,3-bis(indazol-1-ylmethyl)benzene (7).

12

,

12

’

7,

7’,

10,

10’

, 4

1,

8,

8’,

9,

9’

2,

2’

5,

5’

Figure S2. 13

C NMR (100.6 MHz, DMSO-d6) of 1,3-bis(indazol-1-ylmethyl)benzene (7).

Figure S3. HSQC of 1,3-bis(indazol-1-ylmethyl)benzene (7).

4

6, 6’

3, 3’ 1

8, 8’, 9, 9’ 12, 12’, 11, 11’, 2, 2’, 7, 7’

10, 10’

5, 5’

6,

6’

3,

3’

1,

4,

8,

8’

9,

9’,

12,

12’

11,

11’

, 2,

2’,

7

10,

10’

5,

5’

Figure S4. HRMS (FTMS + pESI) m/z of 1,3-bis(indazol-1-ylmethyl)benzene (7).

Figure S5. FTIR (KBr) of 1,3-bis(indazol-1-ylmethyl)benzene (7).

Figure S6. 1H NMR (400.1 MHz, DMSO-d6) of dichloro[3,5-bis(3,5-dimethylpyrazol-1-ylmethyl)toluene-

NN]zinc(II) (11).

Figure S7. MS (FTMS + IT) m/z of dichloro[3,5-bis(3,5-dimethylpyrazol-1-ylmethyl)toluene-NN]zinc(II) (11).

DMT Zn #1507 RT: 11.71 AV: 1 NL: 4.41E3T: ITMS + c ESI Z ms [444.00-450.00]

444.0 444.5 445.0 445.5 446.0 446.5 447.0 447.5 448.0 448.5 449.0 449.5 450.0

m/z

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100

Re

lative

Ab

un

da

nce

445.03

444.57444.11

445.57

445.32444.33444.79

446.08

447.50

448.46447.83

446.29445.78 446.68

446.87 449.71

447.03448.74 448.95

448.05

447.21

446.45 449.48

449.24 449.93

448.21

Figure S8. FTIR (KBr) of dichloro[3,5-bis(3,5-dimethylpyrazol-1-ylmethyl)toluene-NN]zinc(II) (11).

Figure S9. 1H NMR (400.1 MHz, DMSO-d6) of dichloro[2,6-bis(benzotriazol-1-ylmethyl)pyridine-NN]zinc(II)

(12).

Figure S10. MS (FTMS + IT) m/z of dichloro[2,6-bis(benzotriazol-1-ylmethyl)pyridine-NN]zinc(II) (12).

Figure S11. FTIR (KBr) of dichloro[2,6-bis(benzotriazol-1-ylmethyl)pyridine-NN]zinc(II) (12).

BTP Zn #139 RT: 5.05 AV: 1 NL: 1.43E2T: ITMS + p ESI Full ms [400.00-2000.00]

512 514 516 518 520 522 524 526 528 530 532 534 536 538

m/z

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100

105

110

Re

lative

Ab

un

da

nce

526.09

530.18

536.36

517.82 531.27

537.55

533.36 535.36532.00534.73

522.00518.18 528.45

517.09532.36525.55511.73

529.00523.55

524.91523.09518.91

527.00520.45 537.91

514.36 516.36512.18

521.18515.09512.91

Figure S12. 1H NMR (400.1 MHz, DMSO-d6) of dichloro[3,5-bis(benzotriazol-1-ylmethyl)toluene-NN]zinc(II)

(13).

Figure S13. MS (FTMS + IT) m/z of dichloro[3,5-bis(benzotriazol-1-ylmethyl)toluene-NN]zinc(II) (13).

BTT-Zn #35 RT: 0.42 AV: 1 NL: 8.86E2T: ITMS + p ESI Full ms [180.00-2000.00]

200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000

m/z

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100

Re

lative

Ab

un

da

nce

256.50

590.25

445.17

301.83

377.17

454.75 532.83

474.92 1140.83706.58 1693.251600.171477.751062.08 1855.58621.25 1311.00780.75 1958.83961.50912.25 1369.00 1615.67 1721.081255.00

Figure S14. FTIR (KBr) of dichloro[3,5-bis(benzotriazol-1-ylmethyl)toluene-NN]zinc(II) (13).

Figure S15. 1H NMR (400.1 MHz, DMSO-d6) dichloro[1,3-bis(indazol-1-ylmethyl)benzene-NN]zinc(II) (14).

Figure S16. MS (FTMS + IT) m/z of dichloro[1,3-bis(indazol-1-ylmethyl)benzene-NN]zinc(II) (14).

Figure S17. FTIR (KBr) of dichloro[1,3-bis(indazol-1-ylmethyl)benzene-NN]zinc(II) (14).

JHB_02062015B1 #21-25 RT: 0.14-0.17 AV: 5 NL: 8.10E2T: ITMS + p ESI SIM ms [425.00-525.00]

425 430 435 440 445 450 455 460 465 470 475 480 485 490 495 500 505 510 515 520 525

m/z

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

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100

Re

lative

Ab

un

da

nce

437.17

439.08

441.17

522.67

474.83

472.83

471.08494.75

499.17443.08

476.92 501.08

515.33

430.42

521.17503.08447.08514.00478.75 519.17

463.08 493.00 505.00 509.08458.92 487.25448.17428.42 483.50 510.92

469.08432.92 455.25

Figure S18. TGA of dichloro[bis(3,5-dimethylpyrazole-NN)]zinc(II) (8).

Figure S19. TGA of dichloro[bis(3,5-dimethyl-1-pyrazolyl)methane-NN]zinc(II) (9).

-3.4

-2.9

-2.4

-1.9

-1.4

-0.9

-0.4

0.1 -90

-80

-70

-60

-50

-40

-30

-20

-10

0

0 100 200 300 400 500 600 700

DT

G%

/min

% T

G

°C

-8

-7

-6

-5

-4

-3

-2

-1

0

1 -100

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

0 100 200 300 400 500 600 700

DT

G%

/min

% T

G

°C

Figure S20. TGA of dichloro[bis(1,2,4-triazol-1-yl)methane-NN]zinc(II) (10).

Figure S21. TGA of dichloro[3,5-bis(3,5-dimethylpyrazol-1-ylmethyl)toluene-NN]zinc(II) (11).

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4 -30

-25

-20

-15

-10

-5

0

0 100 200 300 400 500 600 700

DT

G%

/min

% T

G

°C

-15.7

-13.7

-11.7

-9.7

-7.7

-5.7

-3.7

-1.7

0.3 -80

-70

-60

-50

-40

-30

-20

-10

0

0 100 200 300 400 500 600 700

DT

G%

/min

% T

G

°C

Figure S22. TGA of dichloro[3,5-bis(benzotriazol-1-ylmethyl)toluene-NN]zinc(II) (13).

Figure S23. TGA of dichloro[bis(3,5-dimethyl-1-pyrazolyl)methane-NN]copper(II) (15).

-6.7

-5.7

-4.7

-3.7

-2.7

-1.7

-0.7

0.3 -55

-50

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

0 100 200 300 400 500 600 700

DT

G%

/min

% T

G

°C

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

-80

-70

-60

-50

-40

-30

-20

-10

0

0 100 200 300 400 500 600 700

DT

G%

/min

% T

G

°C

Figure S24. TGA of dichloro[bis(3,5-dimethyl-1-pyrazolyl)methane-NN]cobalt(II) (16).

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-7.00

-6.00

-5.00

-4.00

-3.00

-2.00

-1.00

.00

1.00

2.00 -45

-40

-35

-30

-25

-20

-15

-10

-5

0

5

0 100 200 300 400 500 600 700

DT

G%

/min

% T

G

°C